Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120.
RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopr opyl)-L-phenylalanine benzyl ester) is a full inhibitor of the enkephalin-catabolizing enzymes, which induces strong naloxone-reversible antinociceptive responses after i.v. or i.p. administration, but is only slightly active after oral administration. Chemical modifications were introduced on this compound, resulting in molecules such as RB 120 (N-((S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxoprop yl)-L-alanine benzyl ester), which was selected for a complete study, after oral administration, in various assays commonly used to select analgesics: mouse hot plate test, rat tail-flick test, electrical stimulation of the tail in rats, paw pressure test on inflamed paws in rats, acetic acid-induced writhing test and the formalin test in mice. RB 120 induced potent dose-dependent antinociceptive responses in all these tests after oral administration. The differences in antinociceptive effects induced by RB 120 in the various assays is probably related to the amount of enkephalins released and to the efficiency of peptidase inactivation in particular brain regions implicated in the control of a given nociceptive input. The goal of discovering orally active analgesics endowed with a potency similar to that of morphine but devoid of its major side-effects, seems now to have been reached with mixed neutral endopeptidase/aminopeptidase N (NEP/APN) inhibitors, although these compounds have yet to be evaluated in clinical trials.
Noble
Florence
F
Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS, URA D 1500, Université René Descartes, UFR des Sciences Pharmaceutiques et Biologiques 4, Avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Smadja
Claire
C
Valverde
Olga
O
Maldonado
Rafaël
R
Coric
Pascale
P
Turcaud
Serge
S
Fournié-Zaluski
Marie-Claude
MC
Roques
Bernard P
BP
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004220:Disulfides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004745:Enkephalins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006358:Hot Temperature; D007249:Inflammation / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical
D004220:Disulfides; D004745:Enkephalins; D004791:Enzyme Inhibitors; C110978:RB 120; D000409:Alanine